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Optimized Left Ventricular Endocardial Stimulation Is Superior to Optimized Epicardial Stimulation in Ischemic Patients With Poor Response to Cardiac Resynchronization Therapy A Combined Magnetic Resonance Imaging, Electroanatomic Contact Mapping, and Hem

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Optimized Left Ventricular Endocardial

Stimulation Is Superior to Optimized

Epicardial Stimulation in Ischemic Patients

With Poor Response to Cardiac

Resynchronization Therapy

A Combined Magnetic Resonance Imaging,

Electroanatomic Contact Mapping, and Hemodynamic Study

to Target Endocardial Lead Placement

Jonathan M. Behar, MBBS, BSC, Tom Jackson, MBBS, Eoin Hyde, PHD, Simon Claridge, LLB, MBBS,

Jaswinder Gill, MD, Julian Bostock, PHD, Manav Sohal, MBBS, Bradley Porter, MBBS, Mark O’Neill, MD, DPHIL, Reza Razavi, MD, Steve Niederer, DPHIL, Christopher Aldo Rinaldi, MD

JACC: CLINICAL ELECTROPHYSIOLOGY CME This article has been selected as the month’s JACC: Clinical Electrophysiology CME activity, available online atwww.jacc-electrophysiology.orgby selecting the CME on the top navigation bar.

Accreditation and Designation Statement

The American College of Cardiology Foundation (ACCF) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

The ACCF designates this Journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit(s). Physicians should only claim credit commensurate with the extent of their participation in the activity.

Method of Participation and Receipt of CME Certificate

To obtain credit for JACC: Clinical Electrophysiology CME, you must: 1. Be an ACC member or JACC: Clinical Electrophysiology subscriber. 2. Carefully read the CME-designated article available online and in this

issue of the journal.

3. Answer the post-test questions. At least 2 out of the 3 questions provided must be answered correctly to obtain CME credit. 4. Complete a brief evaluation.

5. Claim your CME credit and receive your certificate electronically by following the instructions given at the conclusion of the activity.

CME Objective for This Article:Recall the theoretical benefit for left ventricular endocardial over epicardial stimulation for the delivery of biventricular pacing.

CME Editor Disclosure:CME Editor Smit Vasaiwala, MD, has nothing to declare.

Author Disclosures:Drs. Behar and Claridge acknowledge the fellowship support of the NIHR BRC at Guy’s and St Thomas’ NHS Foundation Trust. Dr. Claridge has received research fellowship funding from St. Jude Medical Ltd. Dr. Jackson has received research fellowship funding from Medtronic Inc. Dr. Sohal has received an educational grant from St. Jude Medical Ltd. Dr. Rinaldi is consultant to St Jude Medical Ltd., Medtronic, and Spectranetics; and receives research funding from St Jude Medical and Medtronic.

Medium of Participation:Print (article only); online (article and quiz).

CME Term of Approval

Issue Date: December 2016 Expiration Date: November 30, 2017

From the Department of Imaging Sciences and Biomedical Engineering, King’s College London & Guy’s and St Thomas’ Hospital, London, United Kingdom. Wellcome Trust grant WT088641/Z/09/Z was awarded to Dr. Niedererin. Drs. Behar and Claridge acknowledge the fellowship support of the NIHR BRC at Guy’s and St Thomas’ NHS Foundation Trust. Dr. Claridge has received research fellowship funding from St. Jude Medical Ltd. Dr. Jackson has received research fellowship funding from Medtronic Inc. Dr. Sohal has received an educational grant from St. Jude Medical Ltd. Dr. Rinaldi is consultant to St Jude Medical Ltd., Medtronic, and Spectranetics; and receives research funding from St Jude Medical and Medtronic.

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Optimized Left Ventricular Endocardial

Stimulation Is Superior to Optimized

Epicardial Stimulation in Ischemic Patients

With Poor Response to Cardiac

Resynchronization Therapy

A Combined Magnetic Resonance Imaging,

Electroanatomic Contact Mapping, and Hemodynamic Study

to Target Endocardial Lead Placement

Jonathan M. Behar, MBBS, BSC, Tom Jackson, MBBS, Eoin Hyde, PHD, Simon Claridge, LLB, MBBS,

Jaswinder Gill, MD, Julian Bostock, PHD, Manav Sohal, MBBS, Bradley Porter, MBBS, Mark O’Neill, MD, DPHIL, Reza Razavi, MD, Steve Niederer, DPHIL, Christopher Aldo Rinaldi, MD

ABSTRACT

OBJECTIVESThe purpose of this study was to identify the optimal pacing site for the left ventricular (LV) lead in ischemic patients with poor response to cardiac resynchronization therapy (CRT).

BACKGROUNDLV endocardial pacing may offer benefit over conventional CRT in ischemic patients.

METHODSWe performed cardiac magnetic resonance, invasive electroanatomic mapping (EAM), and measured the acute hemodynamic response (AHR) in patients with existing CRT systems.

RESULTSIn all, 135 epicardial and endocardial pacing sites were tested in 8 patients. Endocardial pacing was superior to epicardial pacing with respect to mean AHR (% change in dP/dtmaxvs. baseline) (11.81 [-7.2 to 44.6] vs.

6.55 [-11.0 to 19.7]; p¼ 0.025). This was associated with a similar first ventricular depolarization (Q-LV) (75 ms [13 to 161 ms] vs. 75 ms [25 to 129 ms]; p¼ 0.354), shorter stimulation–QRS duration (15 ms [7 to 43 ms] vs. 19 ms [5 to 66 ms]; p¼ 0.010) and shorter paced QRS duration (149 ms [95 to 218 ms] vs. 171 ms [120 to 235 ms]; p< 0.001). The mean best achievable AHR was higher with endocardial pacing (25.64  14.74% vs. 12.64  6.76%; p¼ 0.044). Furthermore, AHR was significantly greater pacing the same site endocardially versus epicardially (15.2 10.7% vs. 7.6  6.3%; p ¼ 0.014) with a shorter paced QRS duration (137  22 ms vs. 166  30 ms; p < 0.001) despite a similar Q-LV (70 38 ms vs. 79  34 ms; p ¼ 0.512). Lack of capture due to areas of scar (corroborated by EAM and cardiac magnetic resonance) was associated with a poor AHR.

CONCLUSIONSIn ischemic patients with poor CRT response, biventricular endocardial pacing is superior to epicardial pacing. This may reflect accessibility to sites that cannot be reached via coronary sinus anatomy and/or by access to more rapidly conducting tissue. Furthermore, guidance to the optimal LV pacing site may be aided by modalities such as cardiac magnetic resonance to target delayed activating sites while avoiding scar. (J Am Coll Cardiol EP 2016;2:799–809) © 2016 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

C

ardiac resynchronization therapy (CRT) is a

highly effective treatment for patients with heart failure, severe left ventricular (LV)

impairment and a prolonged QRS duration (1–3).

Despite advancing techniques a substantial proportion of individuals do not derive clinical benefit (4). Improving CRT response is particularly challenging in

ischemic patients because epicardial LV lead place-ment within myocardial scar has a negative impact

(5,6)and avoiding scarred regions may improve CRT response(7). Furthermore, correction of electrical dys-synchrony through targeting of the latest point of acti-vation may be important in improving CRT response

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which is not constrained to the epicardial coronary venous anatomy, may provide superior hemody-namics (10–12) and improved CRT response, which may be of particular benefit in ischemic patients and nonresponders to conventional CRT(12–14). The site of optimal LVendo stimulation is highly variable in ischemic and nonischemic groups(15)with no reliable method to guide optimal LVendo lead placement. Car-diac magnetic resonance (CMR) could potentially iden-tify the target for LV lead placement, being able to delineate scar and dyssynchrony(7). Endocardial con-tact mapping can demonstrate exquisite detail of endocardial activation as well as location and size of myocardial scar. Because patients with ischemic car-diomyopathy and myocardial scar have the poorest response to CRT and the most to gain from LVendo pac-ing, advanced imaging and mapping modalities may be able to guide the optimal site for endocardial LV lead delivery.

We hypothesized that in a group of ischemic patients (with demonstrable myocardial scar on CMR) and a high prevalence of CRT nonresponse, LVendo pacing would produce a superior hemodynamic response compared with the optimal epicardial response (LVepi). Furthermore, by pacing multiple sites, we sought to investigate whether the optimal site of LV stimulation (both epicardially and endocardially) could be predicted on the basis of scar and/or the latest point of electrical activation. By comparing endocardial contact mapping data with CMR, we further sought to elucidate the mechanisms of improved response with LVendo pacing and whether these imaging modalities could be used to guide the optimal LVendo pacing sites.

METHODS

The study complied with the Declaration of Helsinki and the protocol was approved by the local ethics committee. Informed consent was obtained from each patient. Patients with ischemic cardiomyopathy (judged by significant coronary artery disease and

myocardial fibrosis on CMR), QRS duration of

<150 ms, and previously implanted CRT (mean duration of implant 26 21 months) have a pheno-type of suboptimal response to CRT and were inten-tionally selected for study (3). Baseline assessment before CRT implant included clinical assessment (New York Heart Association functional class), 12-lead electrocardiogram, and 2-dimensional echocardiog-raphy. Patients underwent an extensive endocardial mapping protocol and acute hemodynamic study. CMR data were compared with contact mapping and

hemodynamic data findings to compare

optimal LVendo and LVepi pacing locations. HEMODYNAMIC AND ELECTROANATOMIC STUDY. Cases were performed under conscious sedation (mean 2.5 mg midazolam and 3 mg morphine) between March and December 2014. Patients with a mechanical aortic valve or significant peripheral vascular disease were excluded. CMR before CRT was performed with a standardized protocol including cine imaging and delayed enhance-ment sequences in both long and short axis views. Delayed enhancement was performed 10 to 15 min after administration of 0.2 mmol/ kg Gadovist (Bayer Healthcare, Berlin, Ger-many) to identify myocardialfibrosis. Contact LV endocardial scar mapping was performed in sinus rhythm with a roving decapolar cath-eter (6-F Livewire medium sweep 115 cm; St Jude Medical, Sylmar, California) via femoral arterial access with a retrograde aortic approach and displayed using EnSite Velocity NavX system (St Jude Medical, Inc., St Paul, Minnesota). Multiple contact points were taken to create the endocardial geometry (mean 328 133) with particular focus of delineating areas of scar. Points with a sensed bipolar electrogram amplitude of <0.5 mV were defined as scar and colored grey, points>1.5 mV were defined as representing healthy tissue and colored purple and those points in between defined as border zone with a color range(16).

Temporary placement of a high right atrial quad-ripolar catheter was used for atrial sensing. Initially, the optimal epicardial site with atrial synchronous biventricular pacing was assessed using the patient’s chronically implanted LV lead (LVepi1) and a second, temporary epicardial LV lead placed via the femoral vein (LVepi2) to allow multiple epicardial pacing sites from different veins and along the same vein (Figure 1). The optimal endocardial site was then assessed using the roving LV endocardial decapolar catheter. The LV was divided into 12 locations (ante-rior, lateral, infe(ante-rior, septal at basal, mid and apical levels) and randomized (Microsoft Excel). We plan-ned to pace in each of these 12 regions per patient; in addition, extra positions in or adjacent to scar on the EAM were obtained. The mean number of endocardial positions was 10.4  4.8 (range 4 to 18) and each patient had a minimum dataset comprising an anterior, lateral, inferior, and septal position. In all patients, we performed biventricular pacing at cor-responding positions endocardially and epicardially at 2 sites (i.e., LVendo pacing opposite both epi1 and epi2). We usedfluoroscopy (both left anterior oblique SEE PAGE 810

A B B R E V I A T I O N S A N D A C R O N Y M S AHR= acute hemodynamic response CMR= cardiac magnetic resonance CRT= cardiac resynchronization therapy EAM= electroanatomic mapping LV= left ventricle/ventricular LVendo= left ventricular endocardium

LVepi= optimal epicardial response

LVepi1= implanted LV lead LVepi2= temporary LV lead Q-LV=first ventricular depolarization

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and right anterior oblique views) to show the position of the decapolar catheter in relation to the implanted leads and corroborated this with the 3-dimensional geometric shell on EAM to confirm its anatomic position with respect to an AHA 16-segment model. We confirmed the decapolar catheter tip was in a stable,fixed position before commencing our pacing protocol. Prior experience with this equipment has

demonstrated stable electrode localization with

mean change in position of 0.2 1.7 mm (x axis), 0.1  0.3 mm (y axis), and 0.2 0.6 mm (z axis)(17).

The acute hemodynamic response (AHR) was measured using an 0.014-inch high-fidelity Certus RADI PressureWire in the LV as previously described

(11). Atrial pacing 10 bpm greater than the intrinsic rate was used as baseline and compared with con-ventional epicardial biventricular pacing via the implanted LV lead (LVepi1), the temporary LV lead (LVepi2), and biventricular endocardial pacing (LVendo) at multiple sites. A delay of 20 s was respected after changing the pacing protocol and before any measurement to allow for a steady state

(18,19). Points either side of an ectopic beat were removed manually after each case. Atrioventricular delays werefixed at 100 ms and ventriculoventricular delay was set to 0 ms (simultaneous stimulation from both right and left ventricular lead poles). For each pacing site and endocardial position, we measured LV

dP/dtmax (AHR, mm Hg/s), sensed LV electrogram

amplitude (mV), sensed electrical delay (first

ventricular depolarization [Q-LV]) in sinus rhythm (ms), stimulation-QRS onset (ms), and paced QRS duration (ms). Default band passfilter settings of 30 to 300 Hz were used to measure a sensed, bipolar

peak-to-peak voltage signal for the temporary

epicardial LV lead (LVepi2) and endocardial catheter (LVendo) on the EnSite Velocity NavX system. The sensed LV signal from the implanted (LVepi1) lead was obtained through a printed recording from the pacing systems analyzer with manual calculation of the peak-to-peak signal. We identified whether pac-ing locations were in or adjacent to myocardial scar identified on the EAM and CMR and measured the distance between the LV tip and the central scar zone for each data point. Field scaling was applied to ac-count for impedance anomalies and to ensure a 1:1 representation of the patient’s cardiac geometry (EnSite Velocity NavX system). An AHR was deemed positive at a pacing location if the dP/dtmaxincreased

by>10% compared with baseline measurements(20). STATISTICAL METHODS. Continuous variables with a Gaussian distribution were described using mean SD. Categorical data were described by an absolute number of occurrences and associated frequency (%). Acute hemodynamic and electrical data passed the Shapiro-Wilk test for normality. To account for the clustering of data and multiple measurements within each patient, a mixed effect model was applied for all data points that achieved capture. For the best and worst achievable AHR per patient, in addition to endocardial opposite F I G U R E 1 Fluoroscopic and Electroanatomic Imaging of the Study Protocol

(A) Fluoroscopic image of the invasive protocol. (B) Corresponding electroanatomic endocardial, contact scar map using a decapolar left ventricular (LV) catheter and the EnSite Velocity NavX system (St. Jude Medical, Inc., St. Paul, Minnesota); right anterior oblique (left) and left anterior oblique (right) projections. Data points with a sensed electrogram amplitude of<0.5 mV were defined as scar (grey), those with voltage of>1.5 mV were defined as healthy tissue (purple) and those points in between were in the scar border zone with a color range. The anterior surface of the heart in the left panel has been removed to see the location of the endocardial catheter (green) and distal tip (green circle). The epicardial pacing (LVepi)2 lead is in an anterior vein and displayed in blue on the EAM. In addition, the position of the implanted (LVepi)1 lead is shown onfluoroscopy and has been superimposed on the electroanatomic map in both views. Epi ¼ epicardial pacing; HRA¼ high right atrial; LVEndo ¼ endocardial pacing; RA ¼ right atrial; RADI ¼ LV pressure wire; RV ¼ right ventricular.

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epicardial AHR data, mean differences between epicar-dial and endocarepicar-dial datasets were compared with a 2-tailed, paired t test. Analysis of variance was per-formed to compare the means of several groups. Results were considered significant at p < 0.05. Analysis was performed on PASW Statistics 22 (SPSS Inc., Chicago, Illinois) and Stata (Stata Corp., College Station, Texas).

RESULTS

Mean native QRS duration was 140 7 ms on surface ECG. Seven patients (88%) were labelled as having left bundle branch block; however, only 3 (38%) fulfilled the stricter Strauss criteria(21). All patients, however, had evidence of myocardialfibrosis on CMR. Patient demographics are shown inTable 1. Procedural time was 160 45 min and there were no procedural com-plications. Patients had severe LV dysfunction with a

mean ejection fraction of 27%, with minimal

improvement at 6 months (ejection fraction 29%). A total of 135 epicardial and endocardial pacing sites were tested in 8 patients, 119 of which produced cap-ture allowing electrical and hemodynamic assessment. The remaining 16 data points did not capture the ventricle at maximal (10 V) output and were located in regions of scar on the contact map. The mean number of epicardial pacing sites was 5.8 0.5 and the mean number of LVendo positions was 10.4 4.8, including sites where LV capture was unsuccessful.

ACUTE HEMODYNAMIC RESPONSE. Using a mixed effect model analysis for all data points, the mean AHR of LVendo positions (11.81% [range -7.2% to

44.6%]) was significantly superior to the mean AHR of LVepi positions (6.55% [range -11.0% to 19.7%]; p¼ 0.025) (Tables 2 and 3,Online Table 1,Figure 2). This was associated with an identical Q-LV between groups (LVendo 75 ms [range 13 to 161 ms] vs. LVepi 75 ms [range 25 to 129 ms]; p¼ 0.354) but a shorter stimulation-QRS duration (LVendo 15 ms [range 7 to 43 ms] vs. LVepi 19 ms [range 5 to 66 ms]; p¼ 0.010) and paced QRS duration (LVendo 149 ms [range 95 to 218 ms] vs. LVepi 171 ms [range 120 to 235 ms]; p< 0.001). The mean of the best achievable AHR at the optimal LVendo site was significantly higher than the optimal LVepi pacing site (25.64  14.74% vs. 12.64 6.76%; p ¼ 0.044). This was associated with a trend toward a longer Q-LV (95 38 ms vs. 67  33 ms; p ¼ 0.216), shorter stimulation-QRS duration

T A B L E 3 Mean Differences Between Epicardial and Endocardial Datasets

Epicardial Endocardial p Value Best achievable AHRs in

each patient

(N¼ 8) (N¼ 8)

Mean change in AHR (%) 12.64 6.76 25.64 14.74 0.044

Mean QLV (ms) 67 33 95 38 0.216

Mean stimulation-QRS duration (ms)

19 8 14 5 0.126

Mean paced QRS duration (ms) 167 33 137 26 0.002

Worst AHR in each patient (N¼ 8) (N¼ 8)

Mean change in AHR (%) 0.80  6.81 0.93  3.79 0.964

Mean QLV (ms) 68 39 59 15 0.556

Mean stimulation-QRS duration (ms)

26 21 16 4 0.187

Mean paced QRS duration (ms) 174 32 154 34 0.164

Comparison of LVendo opposite the corresponding position of LVepi1 and LVepi2

(N¼ 16) (N¼ 16)

Mean change in AHR (%) 7.60 6.3 15.2 10.7 0.014

Mean QLV (ms) 79 34 70 38 0.512

Mean stimulation-QRS duration (ms)

20 13 16 7 0.214

Mean paced QRS duration (ms) 166 30 137 22 <0.001

Values are mean SD.

LVendo¼ endocardial pacing; LVepi ¼ epicardial pacing; other abbreviations as inTables 1 and 2. T A B L E 2 Mixed Effect Model

Mean Difference 95% Confidence Interval p Value Change in AHR (%) 4.23 0.52 to 7.93 0.025 QLV (ms) 5.92 18.45 to 6.60 0.354 Stimulation-QRS duration (ms) 3.70 6.50 to 0.88 0.010 Paced QRS duration (ms) 25.45 33.59 to 17.32 <0.001

Mixed effect model for all data points achieving capture comparing epicardial and endocardial pacing across the dependent variables as shown. A total of 32 epicardial and 87 endocardial data points were compared across 8 patients.

AHR¼ acute hemodynamic response; QLV ¼ first ventricular depolarization (earliest onset QRS duration on surface 12 lead electrocardiogram) to the nadir signal on the LV lead electrogram.

T A B L E 1 Demographic Data, Pre-CRT and Post-CRT Outcomes (N¼ 8)

Age (yrs) 71 7.4

Male (%) 8 (100)

LVEF by 2D echocardiography Simpson’s biplane before CRT

27 7.4

SDI derived from echocardiography (%) 19

NYHA functional class II/III, before CRT implantation 2/6

Ischemic etiology 8 (100)

Sinus rhythm 8 (100)

QRS duration (m) 140 7

LBBB 7 (88)

LBBB by revised Strauss criteria 3 (38)

Echo responders at 6 months* 2 (25)

LVEF by 2D echo, Simpson’s biplane after CRT 29 7.9

Clinical responders at 6 months† 3 (38)

Values are mean SD or n (%). *Echocardiographic response using 2D trans-thoracic echocardiography; confirmed if $15% reduction in end-systolic volume (ESV) at 6 months’ follow-up compared with before implantation. †Clinical response to CRT using Packer’s clinical composite score(26).

2D¼ 2-dimensional; CRT ¼ cardiac resynchronization therapy; LBBB ¼ left bundle branch block; LVEF¼ left ventricular ejection fraction; NYHA ¼ New York Heart Association.

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(14 5 ms vs. 19  8 ms; p ¼ 0.126) and a shorter paced QRS duration (137  26 ms vs. 167  33 ms; p¼ 0.002). The difference between the best versus worst LVepi site was highly significant (p ¼ 0.0014) as it was for best versus worst LVendo (p ¼ 0.0002). There was a greater difference between the best and worst AHR with LVendo pacing compared with LVepi pacing 26.57  12.58 vs. 13.44  9.00; p ¼ 0.03. There was a nonsignificant trend toward an improved AHR with basal compared with mid and apical posi-tions at all sites (LVepi and LVendo) (base 13.7 11, mid 8.1 9.8, apex 9.6  12.7; p ¼ 0.07).

OPTIMAL LV SITE LOCATION. Epicardial stimulation sites were limited according to the coronary venous anatomy and the best achievable epicardial pacing locations were therefore confined to the AHA seg-ments subtended by these veins. In 7 of 8 patients, the optimal LVepi pacing site was inferolateral/ inferior; in the other patient the basal anterior site was best in keeping with the belief that pacing from the inferolateral/inferior wall is the optimal site of epicardial stimulation in the majority of subjects. LVendo pacing was not limited to the distribution of the coronary veins and there was substantial indi-vidual variation in the optimal site producing the best AHR (Figure 3).

F I G U R E 3 The Optimal Site for LV Stimulation During Biventricular Pacing

Optimal endocardial (left) and epicardial (right) sites (by acute hemodynamic response [AHR]) for placement of the LV lead in the 8 patients. Black circles with a yellow circumference represent the best overall location (LVendo vs. LVepi). This demonstrates that in 6 patients, LVendo pacing produced the best AHR and the optimal locations were dispersed throughout the geometry of the LVendo. Two patients had the best AHRs achieved with LVepi pacing; as can be seen the pacing locations were clustered due to the constraints of the epicardial veins. AHA¼ American Heart Association; ANT¼ anterior; ANT LAT ¼ anterior lateral; POST ¼ posterior; POST LAT ¼ posterior lateral; SEPT ¼ septal; other abbreviations as inFigure 1.

F I G U R E 2 Electroanatomic Contact Scar Map With Associated Acute Hemodynamic Responses During Biventricular Pacing at Different Sites

Anteroposterior (left) and left anterior oblique (right) projections. Data points with a sensed electrogram amplitude of<0.5 mV were defined as scar (grey), those with voltage >1.5 mV were defined as healthy tissue (purple), and those points in between were in the scar border zone with a color range. The best epicardial (LVepi1 and LVepi2) acute he-modynamic response (% change in dP/dt, mm Hg compared with baseline during biven-tricular pacing) is displayed alongside 5 endocardial (LVendo) positions. Abbreviations as in

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ENDOCARDIAL PACING OPPOSITE EPICARDIAL LEAD. When the endocardial catheter was placed opposite the pacing tip of the epicardial lead on the basis of screening and EAM (Figure 1) (LVepi1/ posterolateral and LVepi2/anterior vein), the AHR was significantly greater (15.2  10.7% vs. 7.6  6.3%; p¼ 0.014) despite a similar Q-LV (LVendo 70  38 ms vs. LVepi 79 34 ms; p ¼ 0.512); however, the paced QRS duration was significantly shorter with LV endocardial pacing (LVEndo 137  22 ms vs. LVepi 166 30 ms; p < 0.001).

PACING IN SCAR AND LATE ACTIVATED SITES.The voltage amplitude of the LV sensed electrogram signal was lower at LVendo compared with LVepi sites (LVendo 3.84 2.9 mV vs. LVepi 6.68  4.6 mV; p¼ 0.002). Of the LVendo stimulation sites, 16 did not capture and were in scar at a maximal output of 10 V (confirmed by voltage contact mapping and CMR). The mean electrogram amplitude within scar sites with noncapture was 0.18  0.12 mV (n ¼ 16). The optimal hemodynamic LVendo site was not at the site of latest electrical activation on the EAM in 6 of 8 patients (Online Table 1).

DISCUSSION

We studied the optimal site for both LVepi and LVendo stimulation in a cohort of patients with ischemic heart disease with poor response to con-ventional CRT. The principalfindings were as follows. 1. Indiscriminate endocardial pacing was superior to epicardial stimulation, associated with a similarfirst ventricular depolarization, shortened stimulation-QRS duration and shortened paced stimulation-QRS duration. 2. Optimal achievable endocardial AHR was superior

to the optimal achievable epicardial AHR. 3. There was significant interindividual variability of

the position of the optimal LVendo site which was not predicted by the site of latest electrical acti-vation on EAM.

4. Pacing within scar on EAM and CMR (both epicar-dial and endocarepicar-dial positions) resulted in failure to capture and a poor AHR.

5. LVendo stimulation at a site approximating LVepi stimulation resulted in a better AHR and shorter paced QRS duration despite a similar Q-LV. COMPARISON WITH PREVIOUS STUDIES. In keeping with the current study, LVendo pacing has been found to be superior to conventional CRT in both ischemic and nonischemic patients (11–13). Derval et al.(22)found that LVendo pacing was superior to posterolateral LVepi pacing in nonischemic patients

with significant individual variation between the optimal LVendo pacing sites (22). Spragg et al.(10)

undertook EAM and AHR measurement in 11 pa-tients with ischemic heart disease and

dyssynchro-nous heart failure at the time of ventricular

tachycardia ablation and found LVendo was superior to LVepi pacing(10). Our group has shown the supe-riority of LVendo pacing over conventional CRT in a group of ischemic and nonischemic patients(11). The superiority of LVendo pacing over LVepi seems to be reproducible, but with a significant variability in the optimal site between patients in all the aforemen-tioned studies(10–12).

The current study has some important differences

and new findings in comparison with previous

studies that may be of clinical importance. First, our subjects were selected on the basis of having factors associated with a suboptimal response to conven-tional CRT, namely, male sex, ischemic

cardiomyop-athy, myocardial fibrosis (on CMR), and a QRS

duration of 120 to 150 ms. Although all patients were ischemic in the study by Spragg et al.(10), our sub-jects had a narrower QRS duration (140 14.9 ms vs. 176  29 ms). In the prior studies, epicardial biven-tricular pacing was only delivered from a single site in the posterolateral vein. The superiority of LVendo in these studies (10–12) may have, therefore, arisen because the optimal LVepi position was not assessed. In the current study, we rigorously performed epicardial pacing from multiple sites (between and along veins) tofirst determine the optimal LVepi site (mean 5.8 0.5 sites per subject). For the first time ourfindings confirm the superiority of LVendo stim-ulation, when both LVendo and LVepi sites are sys-tematically optimized.Figure 2shows an example of the superiority of LVendo over LVepi pacing even when LVepi pacing produced a good AHR.

A notable finding of the current study was the

superiority of LVendo over LVepi at the same site. Previous studies have suggested no difference in ischemic and nonischemic patients, however we found a significant benefit with endocardial pacing (15.2 10.7% vs. 7.6  6.3%; p ¼ 0.014). Spragg et al.

(10)compared LVendo and LVepi at the same site in 7 patients and found LVendo pacing increased dP/dtmax

by 36% from baseline compared with 29% via LVepi although this increase was not statistically signi fi-cant. These differences may be related to the different population studied, but also that we assessed and optimized LVepi pacing in both the anterior and posterolateral regions. Our data are in keeping with both animal studies(13)and a computer modelling study from our group (14). Finally, our patients had CMR data that could be correlated with

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the results of EAM, which was not the case in the aforementioned studies (Figure 4).

SCAR AND ELECTRICAL ACTIVATION.In the study from Spragg et al.(10), optimal LVendo pacing sites typically were located far from regions of dense scar and in 8 of 11 subjects optimal LVendo sites were not at the site of latest activation. For most patients, optimal pacing sites were located in regions activated neither extremely early nor late during ventricular excitation. The authors concluded the lack of corre-lation between latest endocardial activation sites and optimal pacing sites may reflect a disconnect between electrical and mechanical activation, the impact of regions of slow conduction, and lines of conduction block on optimal pacing sites. Our results support this theory, confirmed by failure to capture the LV at maximal voltage at 16 endocardial sites within scar (on CMR and EAM). Furthermore, the optimal hemo-dynamic LVendo site did not necessarily correlate with the site of latest electrical activation in 6 of 8 patients, as determined on the EAM activation map.

In keeping with thisfinding, the Q-LV at the optimal LVendo sites were not significantly longer than those at the optimal LVepi site. It seems likely that, on the basis of our and other priorfindings, the latest acti-vating site is not necessarily the optimal site to pace with respect to improved hemodynamics. This may be due to localized areas of slow conduction with islands of viable tissue within areas of scar that acti-vate late (and therefore have a long Q-LV). Likewise, when stimulation is performed at that site, impulse propagation is also slow out of this area and does not result in effective resynchronization. An example of this is seen in Figure 5 in a patient with a large circumferential midventricular and apical infarct with areas of late activating tissue within the scar. It is possible that seeking a late activated site may be beneficial, but only if conduction out of that site is not also delayed or blocked by regions of scar. This is analogous to a Goldilocks effect where the optimal site in ischemic patients because of scar/slow con-duction may be not too early, not too late but just right, somewhere in between the two.

F I G U R E 4 Local Activation Map, Correlation With Myocardial Fibrosis on CMR and Associated AHR at Different Locations in 1 Patient

(Top) Electroanatomic (EAM) contact map showing local activation in the same subject as inFigure 2. White signifies earliest activation and blue latest activation, demonstrating the basal lateral region as the site of latest electrical delay. In this case, the optimal AHR (star) matched the site of latest electrical delay, which was distant from ischemic scar. (Bottom) Cardiac MR (CMR), late gadolinium enhancement sequences in the short axis, mid ventricular (left), 2-chamber (middle), and 4 chamber (right) views. The white arrows demonstrate areas of thin walled myocardium with associated subendocardial myocardialfibrosis, corresponding to an left anterior descending (LAD) territory myocardial infarction. There is a close correlation between the scar demonstrated on the EAM and that displayed with CMR. (Right) AHA bulls-eye plot diagram with scar (derived from CMR and EAM) spray painted in grey (anterior, LAD infarct). All different positions for the LV lead are demonstrated (both epicardial and endocardial) with the legend detailing whether the associated AHR with biventricular pacing was<10% or >10% improvement from baseline. Pacing around the anterior regions of scar corresponded to a poor AHR, compared with much better AHRs in sites out of scar. Abbreviations as inFigures 1 and 3.

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MECHANISM OF BENEFIT OF LVendo PACING. In-discriminate stimulation of the LVendo produced a superior hemodynamic effect compared with con-ventional epicardial stimulation. The benefit of LVendo pacing may be related to the lack of coronary venous constraints and the ability to access all re-gions of the myocardium resulting in the ability to obtain the best achievable AHR. The broad variation in hemodynamic response and notable lack of capture in areas of scar, clearly visible on CMR/EAM suggest a targeted approach avoiding scar may be helpful. The superiority of the optimal LVendo over the optimal LVepi AHR at the same site with an associ-ated shorter paced QRS duration may support more rapid activation of the ventricles by fast conducting tissue including the His-Purkinje network (14,15). Equally, other mechanisms (not examined in this manuscript) such as a shorter, more concave path for electrical conduction with LVendo pacing may also be contributing to ourfindings.

CLINICAL RELEVANCE. CRT nonresponse occurs in one-third of patients receiving this treatment and is higher in ischemic patients with myocardialfibrosis and modest QRS prolongation (120 to 150 ms). Stra-tegies to improve response in this group are required.

The recently published ALSYNC (ALternate Site Car-diac ResYNChronization) study demonstrated the feasibility and safety of LV endocardial CRT deliv-ered, through the atrial trans-septal approach(23). In 138 patients with either prior suboptimal response to conventional CRT, failure of LV lead implantation or suboptimal coronary venous anatomy the inves-tigators achieved a high implant success rate (89.4%), with stable pacing parameters and an 82.2% freedom from complications at 6 months. Furthermore, clinical and echocardiographic improvement was 59% and 55%, respectively, in a group with prior nonresponse, which is highly encouraging. Targeting the optimal site for LV stimulation remains an important issue given the marked degree of variability between pa-tients. Our results suggest that CMR may be helpful in this respect especially in avoiding areas of scar, which result in failure to capture or poor resynchronization. Targeting a late but not necessarily latest activating site (i.e., late but not within the scar) is achievable with CMR techniques that give information regarding myocardial activation/contraction patterns as well as pinpointing scar(24).

The ALSYNC study used an empirical approach to LV lead placement and despite this reported a sig-nificant improvement compared with conventional F I G U R E 5 Local Activation Map and Associated Acute Hemodynamic Response in a Patient With Electrical Latency Within a

Large Area of Scar

Dilated, globular heart with a heavy burden of myocardial scar. Earliest activation is white and latest activation blue/purple. In this case, LVendo locations were not superior to conventional LVepi with respect to the AHR. The point of latest electrical activation in this case is around the anteroseptum, most likely as a result of slow activation spreading and encircling a large region of scar. Although these sites are the latest activated they will not produce a good AHR because they are in scar and may explain why the latest activated site is not always the optimal pacing site. Abbreviations as inFigures 1 and 3.

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epicardial pacing. Our results support image guidance on the basis that a broad range of AHR values were obtained and therefore not all endocardial positions are equal in this cohort. Although an indiscriminate approach showed endocardial pacing was superior to epicardial pacing (Table 2), an even greater AHR was achievable when both epicardial and endocardial sites were optimized. Therefore, an image-guided, targeted approach could be a strategy for identifying the optimal location for LV lead stimulation. CMR techniques do, however, require further evaluation to assess their merit in guiding endocardial pacing sites and techniques which allow CMR derived scar and mechanical activation to be fused onto live fluoros-copy for epicardial LV lead guidance may also be used for LVendo lead guidance(18,25).

STUDY LIMITATIONS. The main limitation of the current study is the low number of patients studied. Due to the highly invasive nature of the study and the difficulty in identifying a group of nonresponders, this is understandable. The protocol was, however, extremely rigorous with a large number of data points (135 endocardial and epicardial pacing positions). The EAM study is invasive and not likely to be of use in routine clinical practice. Due to the length of the procedures no changes in atrioventricular or ven-triculoventricular delay were studied and it is possible that such manipulations may have produced a different response. Finally, hemodynamic response may not necessarily translate to chronic response to CRT and therefore longer term studies are required; results from a multicenter, randomized, controlled

trial, RADI-CRT (Pressure Wire Guided Cardiac

Resynchronisation Therapy;NCT01464502) may help to clarify this.

CONCLUSIONS

Ourfindings suggest that, in ischemic patients with poor CRT response, endocardial pacing is superior to epicardial pacing with an even greater response achievable with optimization for each set of pro-tocols. The mechanism of benefit may be due to the ability to access more optimal sites that cannot be reached by the constraints of the CS anatomy. Furthermore, guidance to the optimal LV pacing site may be aided by modalities such as CMR to target nonscarred and delayed activating sites.

ACKNOWLEDGMENTS Dr. Behar acknowledges the

support of the Rosetrees trust. The authors

acknowledge the support of Connal Monro and St. Jude Medical for their technical support and guidance

during the clinical cases. The authors also acknowl-edge Abdel Douiri, Kings College London, for statis-tical support.

REPRINT REQUESTS AND CORRESPONDENCE: Dr. Jonathan M. Behar, Imaging Sciences & Biomedical Engineering, St. Thomas’ Hospital, 4th Floor Lambeth Wing, London SE1 7EH, United Kingdom. E-mail:

jonathan.behar@kcl.ac.uk.

PERSPECTIVES

COMPETENCY IN MEDICAL KNOWLEDGE:

Biventricular pacing delivered through LV endocardial stimulation seems to provide superior acute hemody-namics and a shortening of the paced QRS duration compared with LV epicardial stimulation in the equiv-alent territory. A lack of coronary venous constraint and preferential access to fast conducting tissue are likely to under pin the superiority of this method for delivery of CRT. Cardiac magnetic resonance–derived myocardialfibrosis corroborates with scar derived from electroanatomic maps and may be helpful in guiding LV lead placement. Furthermore, targeting nonscarred segments identified through cardiac magnetic reso-nance cine sequences can aid optimal lead placement in an attempt to improve response to CRT.

TRANSLATIONAL OUTLOOK:Biventricular pacing has been offered to selected patients with heart fail-ure for more than 20 years; however, a significant proportion of individuals receiving this therapy do not derive significant clinical benefit. Certain groups such as male patients with ischemic etiology, myocardial scar and QRS duration of 120 to 150 ms have a high prevalence for poor response and alternative options for improving the effectiveness of CRT are urgently required. Recently, animal and human data have suggested superior hemodynamics and shorter elec-trical activation for endocardial versus epicardial LV stimulation in delivery of biventricular pacing. Clinical studies have demonstrated the feasibility of endo-cardial LV stimulation through transatrial septal and transventricular septal approaches, as well as leadless LV pacing in combination with an implanted right-sided system. Coupled with advanced cardiac imaging to guide LV placement away from areas of scar and toward those activating lately, CRT delivery through permanent LV endocardial stimulation may represent a new method to improve outcomes for heart failure patients over the coming decades.

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R E F E R E N C E S

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5.Bleeker GB, Kaandorp TA, Lamb HJ, et al. Effect of posterolateral scar tissue on clinical and echo-cardiographic improvement after cardiac resynch-ronization therapy. Circulation 2006;113:969–76. 6.Ypenburg C, Roes SD, Bleeker GB, et al. Effect of total scar burden on contrast-enhanced mag-netic resonance imaging on response to cardiac resynchronization therapy. Am J Cardiol 2007;99: 657–60.

7.Leyva F, Foley PWX, Chalil S, et al. Cardiac resynchronization therapy guided by late gadolinium-enhancement cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2011;13:29. 8.Khan FZ, Virdee MS, Palmer CR, et al. Targeted left ventricular lead placement to guide cardiac resynchronization therapy: the TARGET study: a randomized, controlled trial. J Am Coll Cardiol 2012;59:1509–18.

9.Saba S, Marek J, Schwartzman D, et al. Echo-cardiography-guided left ventricular lead place-ment for cardiac resynchronization therapy: results of the Speckle Tracking Assisted Resynch-ronization Therapy for Electrode Region trial. Circ Heart Fail 2013;6:427–34.

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12.Padeletti L, Pieragnoli P, Ricciardi G, et al. Acute hemodynamic effect of left ventricular endocardial pacing in cardiac resynchronization therapy: Assessment by pressure-volume loops. Circ Arrhythmia Electrophysiol 2012;5:460–7. 13.Prinzen FW, Van Deursen C, Van Geldorp IE, et al. Left ventricular endocardial pacing improves resynchronization therapy in canine left bundle-branch hearts. Circ Arrhythmia Electrophysiol 2009;2:580–7.

14.Hyde ER, Behar JM, Claridge S, et al. Beneficial effect on cardiac resynchronization from left ventricular endocardial pacing is mediated by early access to high conduction velocity tissue: elec-trophysiological simulation study. Circ Arrhythmia Electrophysiol 2015;8:1164–72.

15.Derval N, Steendijk P, Gula LJ, et al. Optimizing hemodynamics in heart failure patients by sys-tematic screening of left ventricular pacing sites: the lateral left ventricular wall and the coronary sinus are rarely the best sites. J Am Coll Cardiol 2010;55:566–75.

16.Nakahara S, Vaseghi M, Ramirez RJ, et al. Characterization of myocardial scars: electro-physiological imaging correlates in a porcine infarct model. Heart Rhythm 2011;8:1060–7. 17.Wittkampf FH, Wever EF, Derksen R, et al. LocaLisa: new technique for real-time 3-dimensional localization of regular intracardiac electrodes. Circulation 1999;99:1312–7. 18.Shetty AK, Duckett SG, Ginks MR, et al. Cardiac magnetic resonance-derived anatomy, scar, and dyssynchrony fused withfluoroscopy to guide LV lead placement in cardiac resynchronization ther-apy: a comparison with acute haemodynamic measures and echocardiographic reverse remod-elling. Eur Heart J Cardiovasc Imaging 2013;14: 692–9.

19.Ginks MR, Duckett SG, Kapetanakis S, et al. Multi-site left ventricular pacing as a potential treatment for patients with postero-lateral scar: insights from cardiac magnetic resonance imaging and invasive haemodynamic assessment. EuroPace 2011;14:373–9.

20.Duckett SG, Ginks MR, Shetty AK, et al. Inva-sive acute hemodynamic response to guide left ventricular lead implantation predicts chronic remodeling in patients undergoing cardiac resynchronization therapy. J Am Coll Cardiol 2011; 58:1128–36.

21.Strauss DG, Selvester RH, Wagner GS. Defining left bundle branch block in the era of cardiac resynchronization therapy. Am J Cardiol 2011;107: 927–34.

22.Derval N, Bordachar P, Lim HS, et al. Impact of pacing site on QRS duration and its relationship to hemodynamic response in cardiac resynchroniza-tion therapy for congestive heart failure. J Cardiovasc Electrophysiol 2014;25:1012–20. 23.Morgan JM, Biffi M, Gellér L, et al. ALternate Site Cardiac ResYNChronization (ALSYNC): a pro-spective and multicentre study of left ventricular endocardial pacing for cardiac resynchronization therapy. Eur Heart J 2016:ehv723 [E-pub ahead of print].

24.Codreanu A, Odille F, Aliot E, et al. Electro-anatomic characterization of post-infarct scars comparison with 3-dimensional myocardial scar reconstruction based on magnetic resonance imaging. J Am Coll Cardiol 2008;52:839–42. 25.Ma YL, Shetty AK, Duckett S, et al. An inte-grated platform for image-guided cardiac resynchronization therapy. Phys Med Biol 2012;57: 2953–68.

26.Packer M. Proposal for a new clinical end point to evaluate the efficacy of drugs and devices in the treatment of chronic heart failure. J Card Fail 2001;7:176–82.

KEY WORDS cardiac magnetic resonance imaging, CRT, electroanatomic map, endocardial pacing

APPENDIX For a supplemental table, please see the online version of this article.

Go to http://www.acc. org/jacc-journals-cme to take the CME quiz for this article.

References

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